Process for producing a



has beenfurther discovered that the aforementioned startingmaterials may be converted into certain novel brorno 30 dio1-3,20-dione and/oritssesters, may be utilized for the example, they are also intermediates for the production of corresponding ring A unsaturated pregnane compounds used for'the esterification of steroid alcohols. 'ticularly, 'R represents the residue of a lower fatty acid -such=asacetic or propionic :01 the residue of an aromatic 2,735,855 Patented Feb. 21, 1956 United States Patent ICC 2,7355855 In practicing the process above outlined an 11,21-

diester of allopregnan-l1u,2l-diol-3,20-dione prepared in PROCESS FOR PRODUCING M-PREGNEN-llog'llaccordance with our United States application, Serial ?(I)%L-3.,Z0-DIONESANDINTERMEDIATE THERE Number 335,585, filed February 6, 1953, dissolved in a 5 suitable solvent such as glacial acetic acid, is treated with Carl .Dierassi Birmingham Mich and George Rosem two molar equivalents of bromine in acetic acid in the Mexico City, Mexico, assignol-s to A i s presence of .a catalytic amount of hydrogen bromide. tex Incorporated, Hato Rey, Puerto Rico, a corporation Preferably, during the addition of the bromine in acetic of Puerto Rico acid, which took approximately minutes, the tempera- I Y. J 1O ture 'ofithe rnixtureis *keptat room'temperature. After N0 fi gz gga 1953 standing for a suitable length of time, in or'dertocomplete the rearrangement of the 2,-2' dibromo compound first Claims P y, application Mexico March 1952 formed into the more stable '-2;4-dibromo derivative, the 4 Claims (Cl. 260 397 45) solution is dilutedWithwvater -and the'precipitate suitably The present invention relates to novel cyclopenta- The"2,'4=dibromo-derivative-thus"producedis'thentreatnophenanthrene derivatives and to a method for the preped with so'dium iodide inthe presence ofa-lower aliphatic aration thereof.

More particularly, the present invention relates to ring ketone solvent or with =anequivalent alkali metal iodide to prepare the corresponding 2-iodo-A -comp'ound. The

A unsaturated compounds of the pregnene and allopreg- 2-iodo-A -compound is then subjected -to-treatment with name series having 110a and 2l-hydroxy groups and 3 and a-deiodinatingagent, as 'for example,-'chromous chloride, 20-.keto groups, as well as to esters thereof. sodium bisulfite, collidine or a tertiary amine such as In accordance with the present invention, it has been dimethylaniline. The resultant -1121-diester of 'n pregdiscovered that allopregnan-1.la,21-diol-3,20-dione and nen-l-la,2l-diol-3,-20-dione-was"then readily converted into its estersmay be converted into the novel A -allopregnenthefree compound lay conventionalsaponificaition. Mild l1a,21-diol-3,20-dione and esters thereof, the corresponding A -isomers and the corresponding M-pregnen compounds. In accordance with'the present invention, there esterification 10 C.-) vvith-approiimately one-moi ofan esterifyi ng agent, such as acetic anhydride, gave the/corresponding 2l-monoest'er.

The brominated derivatives of allopregnan-llu,17m-

compounds :as well as other certain novel intermediates for theproduction of the final compounds referred to.

The final'products of the present novel process just referred to have 'therapeutic,hormone activity, especially of v u p I, thetype characterizing the adrenal cortical steroids. Fur- 'lofihoin ther, since .the lla-hydroxy group of these final com- 0 pounds may be readily oxidized with chromic acid, for i production of novel ring A unsaturated .steroids such as the corresponding "A land "A -'derivatives,lin accordance withthefollowingtequations:

such as ll-dehydro corticosterone.

The following equation serves to illustrate a portion of Dibromlnation the present invention:

OHr-OR CH2OR i 30 .(JO j i I Dahyarabrommmon on "on Dibromination Br Sodium llodide CHPOR i 30 GHr- OR Rio 'Deiodination I r Mone rBr In the above equation, R preferably represents an acyl bromimtwn group, i. e., the residue of an organic acid conventionally More parpin-on Dhydrbbtonilnfitlou acid such as benzoic. R may also represent hydrogen.

GHQ-OR u In the above equations, R represents the same groups as heretofore set forth.

In proceeding in accordance with the above equations, the starting material which may be a suitable ester, such as the 11,21-diacetate of allopregnan-lla,2l-diol-3,20- dione is treated either with one molar equivalent of bromine or two molar equivalents, depending upon whether dure as previously set forth in connection with the A*- compound.

The following specific examples serve to illustrate, but are not intended to limit the present invention:

Example I A solution of 1 g. of allopregnan-l1a,2l-diol-3,20-dione diacetate in 60 cc. of glacial acetic acid was mixed with three drops of a 4-normal solution of hydrogen bromide in acetic acid and then a solution of 1.05 molar equivalents of bromine in acetic acid was added dropwise and under mechanical stirring. After the solution had decolorized completely, it was diluted with water and the precipitate was collected, washed with water and air dried. The product was 2-bromo-allopregnan-11u,2l-diol-3,20-dione.

Example I] A solution of 1 g. of the Z-bromo compound obtained according to Example I, in 7 cc. of gamma-collidine was refluxed for 45 minutes. The cooled mixture was filtered from the collidine hydrobromide formed (its weight corresponded to 0.97 molar equivalents), the precipitate was washed with ether and the filtrate was diluted with more ether, washed with dilute hydrochloric acid, sodium carbonate solution and water, dried over sodium sulphate and evaporated to dryness. In order to purify the compound, it was dissolved in a mixture of benzenehexane and the solution was passed through a column with 3 g. of alumina previously washed with ethyl acetate. Recrystallization from ethel acetate yielded A -allopregnen-1la,21- diol-3,20-dione.

In the above experiment, gamma-collidine can be substituted by 2,6-lutidine with the same results.

Saponification of the diacetate by refluxing with 1% ethanolic potassium hydroxide during 1 hour and working up in the usual way afforded the free N-allopregnen- 1la,21-diol-3,20-dione. Acetylation of this compound with 1.1 mols of acetic anhydride in pyridine solution at a temperature of 10 C., during 2 daysgave A -allopregnen-lla,2l-diol-3,20-dione 2l-monoacetate.

Example III A solution of 1 g. of the Z-bromo compound obtained according to Example I, 0.75 g. of semicarbazide hydrochloride and 0.8 g. of sodium acetate trihydrate (previously dissolved in 0.5 cc. of water) in 150 cc. of acetic acid was heated for 2 hours at a temperature of 60 C., under atmosphere of nitrogen. After this time, 10 cc. of pyruvic acid, 3 g. of sodium acetate and 20 cc. of water were added and the temperature of the mixture was raised to 75 C. After 2 hours, 4 additional cc. of pyruvic acid were added and the mixture was kept standing overnight. Next day it was diluted with much water and the precipitate was extracted with chloroform, washed with sodium bicarbonate and water, dried over sodium sulphate and evaporated to dryness, thus giving A -allopregnen-11a,2ldiol-3,20-dione diacetate identical to the one obtained according to Example II.

Example IV A solution of 2 g. of the 2-bromo derivative obtained according to Example I and 1.1 molar equivalents of 2,4-dinitrophenylhydrazine in 50 cc. of glacial acetic acid was heated at 100 C., for 5 minutes, the mixture was cooled and the crystals of the orange dinitrophenylhydrazone formed were collected and washed with alcohol. 1 g. of this compound was dissolved in 50 cc. of chloroform and then mixed with 75 cc. of pyruvic acid and 6 cc. of a 4-normal solution of hydrogen bromide in acetic acid. After heating for 3 hours at 60 C., under atmosphere of nitrogen, the mixture was diluted with chloroform and the chloroform layer was washed with water, sodium carbonate solution and water, dried over sodium sulphate and evaporated to dryness. After one crystallization from ethyl acetate, N-allopregnen-l1a,21-diol- 3,20-dione diacetate was obtained, identical to the one obtained according to Example 11.

Example V A solution of 2 g. of allopregnan-l1a,21-diol-3,20-dione diacetate in cc. of glacial acetic acid containing 5 drops of a r-normal solution of hydrogen bromide in acetic acid was treated dropwise at 20 C., under mechanical stirring with a solution of 2 molar equivalents of bromine in 5 cc. of glacial acetic acid which was added in a period of 15 minutes. 1 additional cc. of the hydrogen bromide solution was added and the solution was kept overnight at room temperature in order to complete the rearrangement of the 2,2'-dibromo configuration into the more stable 2,4-dibromo configuration. Next day the mixture was diluted with water and the precipitate of 2,4-dibromoallopregnan-l1a,21-diol-3,20-dione was collected, washed and air dried.

Example VI A solution of 1 g. of the 2,4-dibromo compound obtained according to Example V, in 8 cc. of collidine was refluxed for 40 minutes and then treated by the procedure described in Example II. After one crystallization from ethyl acetate, A -pregnadien-l1a,21-diol-3,20-dione diacetate was obtained.

Saponification by the method described in Example II yielded the free A -pregnadien-11a,21-diol-3,2O-dione and monoacetylation of this compound by the method described in Example H gave n -pregnadien-lla,21-diol- 3,20 dione 21-monoacetate.

Example VII A solution of 3 g. of the 2,4-dibromo compound obtained according to Example V, in 100 cc. of acetone (or methylethyl-ketone) was refluxed for 20 hours with 3.3 g. of sodium iodide. After cooling, the mixture was diluted with ether and washed with sodium thiosulphate solution, sodium bicarbonate and water, dried over sodium sulphate and evaporated to dryness under reduced pressure, leaving as a residue the crude 2-iodo-A -pregnen- 11a,21-diol-3,20-dione diacetate.

Example VIII A solution of 1.5 g. of the crude 2-iodo-A -pregnenl1a,21-diol-3,20-dione diacetate in 200 cc. of acetone was mixed with a solution of chromous chloride prepared "from -1'1 g. of chronic chloride by the method described by Rosenkranz, Mancera, Gatica and Djerassi, J. Am. Chem Soc., 72, 4077 (1950). After 15 minutes at room temperature, the solution was diluted with water and the product was extracted with ether, washed with sodium bicarbonate and water, dried over sodium sulphate and concentrated to a small volume until the product started to crystallize. After cooling the solution, the product was collected and recrystallized from hexaneacetone to give A -pregnen-11a,21-diol-3,20-dione diacetate with a melting point of 148150 C., /a/D+158 (chloroform).

Saponification by the method described in Example .11 aiforded the free A -pregnen-l1u,2l-diol-3,20-dione and monoacetylation of this compound according to the method described in Example II gave A -pregnen-lla,- 21-diol-3,20-di0ne ll-monoacetate.

Example IX 1 g. of the iodo compound obtained according to Example VII was refluxed with 10 cc. of collidine for 30 minutes and the cooled mixture was diluted with ether and washed with dilute hydrochloric acid, sodium earbonate and water, dried over sodium sulphate and evaporated to dryness. The same product was thus obtained, as the one described in Example VIII. In this reaction collidine can be substituted by 2,6-lutidine or dimethylaniline.

We claim:

1. A process for the production of a compound selected from the class consisting of A -pregnen-llalldiol-3,20-dione, lower fatty acid esters thereof and benzoic acid esters thereof which comprises treating a compound selected from the class consisting of allopregnanlla,2l-diol-3,20-dione, lower fatty acid esters thereof and benzoic acid esters thereof with approximately 2 molar equivalents of bromine to form a 2,4-dibromo derivative, treating said dibromo derivative with an alkali metal iodide in the presence of a lower aliphatic ketone to form the corresponding 2-iodo-A -compound and then treating the 2-iodo-A -compound with a deiodinating agent.

2. The process of claim 1, wherein the deiodinating agent is selected from the group consisting of chromous chloride, sodium bisulfite, a tertiary amine and Raney nickel.

3. The process of claim 1, wherein the product is A* pregnen-l1a,2l-diol-3,20-dione 11,2l-diacetate and the starting compound is allopregnan-l1u,2l-diol-3,20-dione 11,21-diacetate.

4. 2,4-dibromo-allopregnan-1la,21-diol-3,20-dione diacetate.

References Cited in the file of this patent UNITED STATES PATENTS 2,602,769 Murray et al. July 8, 1952 

1. A PROCESS FOR THE PRODUCTION OF A COMPOUND SELECTED FROM THE CLASS CONSISTING OF $4-PREGNEN-11A,21DIOL-3,20-DIONE, LOWER FATTY ACID ESTERS THEREOF AND BENZOIC ACID ESTERS THEREOF WHICH COMPRISES TREATING A COMPOUND SELECTED FROM THE CLASS CONSISTING OF ALLOPREGNAN11A,21-DIOL-3,20-DIONE, LOWER FATTY ACID ESTERS THEREOF AND BENZOIC ACID ESTERS THEREOF WITH APPROXIMATELY 2 MOLAR EQUIVALENTS OF BROMINE TO FORM A 2,4-DIBROMO DERIVATICE, TREATING SAID DIBROMO DERIVATIVE WITH AN ALKALI METAL IODIDE IN THE PRESENCE OF A LOWER ALPHATIC KETONE TO FORM THE CORRESPONDING 2-IODO-$4-COMPOUND AND THEN TREATING THE 2-IODO-$4-COMPOUND WITH A DEIODINATING AGENT. 